Lactones



Patented Mar. 22, 1949 I LACTONES Roger J. Williams, Austin, Tex., assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Original application April 3, 1939,

Serial No. 265,799. Divided and this application February 19, 1942, Serial No. 431,531

7 Claims; (cl. zoo-s44) 1 This invention relates to lactones and particularly to the lactone obtained by hydrolytic splitting of pantothenic acid obtained from natural sources. i

2 The crude calcium salt of pantothenic acid thus obtained is hydrolyzed by dissolving it in normal hydrochloric acid and heating the solution for 1 hours at 100 C. The resulting solu- Thi application is a division of my copending 5 tion is evaporated to dryness at 50 and the application Serial No. 265,799, filed April 3, 1939. residue containing the crude lactone is allowed for Preparation of growth promoting substances. to react with an excess of p-alanine-ethyl ester Substances having the physiological activity of for 18 hours at 5. The resulting product, after pantothenic acid may be obtained by condensing hydrolysis of the ester linkage, possesses very ,B-alanine or derivatives thereof, such as its esters high potency for stimulating the growth of yeast and salts, with certain lactones. Among the lacor Streptococcus Zactis. A salt of fl-alanine can tones that have proven useful for this purpose be condensed with this lactone, if desired, inis the lactone obtained by hydrolytic splitting of stead of a p-alanine ester. pantothenic acid obtained from natural sources. The substance used in this example for con- The object of this invention is to provide lacl5 densation with an ester or salt of p-alanine is tones suitable for use in the preparation of suba lactone because although it is neutral it comstances having the physiological properties of bines with alkali like an acid and on warming the pantothenic acid. alkali metal salt with dilute mineral acid the In accordance with the invention, pantothenic original neutral substance is regenerated. It acid is obtained from natural sources in relatively 20 contains an a-hydroxy group because on heatconcentrated form, preferably as an alkali metal ing with concentrated sulphuric acid at about salt. This concentrate is then subjected to hy- 140? for one hour it yields approximately one drolysis by treatment with an acid or alkali, mole of carbon monoxide for one equivalent of whereupon the acid is split into less complicated substance used. This has been found to be a substances, one of which is a lactone. quantitative method for determination of a-hy- In accordance with one specific embodiment of droxy acids. the invention, the autolysate from sheep liver is The molecular weight of pantothenic acid from treated with fullers earth to remove basic subwhich the aforementioned lactone is derived and stances, then brought to about pH 3.5 and the the oxidation equivalent of pantothenic acid, exphysiologically active acid adsorbed by Norite clude the probability that the lactone portion of charcoal. This is eluted with dilute ammonia, the molecule contains more than six carbon neutralized, and evaporated to dryness in the atoms. The crude lactone, above described, may presence of brucine alkaloid, brucine oxalate. and be purified by distillation in a molecular still. infusorial earth. This dry material is ground and When so purified, it reacts with p-alanine and extracted with chloroform and the chloroform derivatives thereof to form a product indisextracted with a small proportion of water. The tinguishable from pantothenic acid in respect to resulting brucine salts, which include the brucine its physiological action. salt of pantothenic acid, are subjected to an This lactone is the laevo rotary form of a-hyelaborate fractionation procedure involving disdroxy-p, B-dimethyl-r-butyro lactone, having the tribution between the two immiscible solvents, formula water and chloroform. The fractions are tested OHPC(UHB), CHOH CO for physiological activity during the process.

The concentrated brucine salts are converted 0 into calcium salts by shaking with lime' water What is claimed is: and the brucine removed by chloroform extrac- 1. The laevo rotary form of a-hydroxy-fltion. The calcium salts are further fractionated m hyl-vyr laCtOnB Substantially free according to the degree of purity desired. using f the O r y formmercuric chloride to remove impurities. and vari- 2. The process which comprises hydrolytic lly ous solvents for fractional precipitation. More Splitting n alkaline e t metal Salt of P ys details of the elaborate process are given in the ol gica y active Dantothenic acid to Sever the following reference: carbonyl-amino linkage therein.

R. J. Williams, J. R. Truesdail, H. H. Weinstock, 3. The process which comprises hydrolytic ly Jr.. E. Rohrmann, G. M. Lyman. and C. H. Mcsplitting the calcium salt of physiologically active Burney. Journal American Chemical Society, vol. pantothenic acid obtained from a natural source to sever the carbonyl-amino linkage therein.

3 4. The process which comprises hydroiytically splitting a concentrate of the calcium salt of 7. The process which comprises hvdrolytically splitting with an acid a concentrate of the calcium salt of physiologically active pantothenic aseasos acid obtained from a natural source to sever the carbonyl-amino linkage therein.

' ROGER J. WIILIAMB.

REFERENCES CITED The following references are 01' record in the file of this patent:

Gilman, Organic Chemistry, vol. 1 (1938), J. Wiley 8: Sons. pages 176, 187-196, 155, 159.

Levine and Haller, J. Biological Chem., vol. 69, page 165 (1926). 7

Journal American Chem. Society, vol. 62, pp. 1779-1784, July 1940.

Monatscheite fur Chemie, vol. 89. DD. 295-296.

Monatscheite fur Chemie, vol. 25. PP. 46-54 (Glaser). 

